US3914221A - {8 (thiophosphonothio)acetamido{9 cephalosporin derivatives - Google Patents

{8 (thiophosphonothio)acetamido{9 cephalosporin derivatives Download PDF

Info

Publication number
US3914221A
US3914221A US258687A US25868772A US3914221A US 3914221 A US3914221 A US 3914221A US 258687 A US258687 A US 258687A US 25868772 A US25868772 A US 25868772A US 3914221 A US3914221 A US 3914221A
Authority
US
United States
Prior art keywords
lower alkyl
hydrogen
aralkyl
acetamido
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US258687A
Inventor
Uwe D Treuner
Hermann Breuer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US258687A priority Critical patent/US3914221A/en
Priority to US05/542,329 priority patent/US3956290A/en
Publication of USB258687I5 publication Critical patent/USB258687I5/en
Application granted granted Critical
Publication of US3914221A publication Critical patent/US3914221A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6544—Six-membered rings
    • C07F9/6547—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • ABSTRACT (Thiophosphonothio)acetamido]cephalosporin derivatives of the general formula [73] Assignee: E. R. Squibb & Sons, Inc.,
  • aryl or certain heterocyclic groups R; and R each is lower alkyl. aryl or aralkyl or R and R may together be two or three methylene groups joining in a 5- or 6-membered ring with theoxygen and phosphorus; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy.
  • X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents.
  • X and R represent a bond linking carbon and oxygen in a lactone ring.
  • R is hydrogen, lower alkyl, alkali metal, trimethy lsilyl or ll -CH2-O-C-R4,
  • R is phenyl, thienyl, furyl or pyridyl, especially phenyl, R, and R; each islower alkyl, especially methyl or ethyl; R is lower alkyl, preferably methyl or t-butyl; and X is preferably hydrogen or acetoxy.
  • the various groups represented by the symbols have one, especially in the para position of the phenyl.
  • Illustrative are phenyl, 0-, mand p-chlorophenyl, o-, mp-bromophenyl, 3,4-dichlorophenyl. 3,5- dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl. p-hydroxyphenyl, pcarboxyphenyl and the like.
  • the aralkyl groups include a monocyclic carbocyclic aryl group attached to a lower alkyl group, both as defined above. lllustrative are benzyl, o-, mor pchlorobenzyl, o-, mor p-bromobenzyl, o-. mor pmethylbenzyl, phenethyl, p-chlorophenethyl, 3,5- diethylbenzyl,3,4,5-trichlorobenzyl and the like.
  • the lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented by X include the acyl group of acid esters.
  • the lower alkanoyl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above.
  • the lower alkanoyloxy groups include, for example, acetoxy, propionyloxy, butyryloxy and the like.
  • the aroyloxy groups are derived from monocyclic carbocyclic aryl groups of the kind described.
  • the aralkanoyloxy groups consist of monocyclic carbocyclic aryl and alkanoyloxy radicals of the type described.
  • the sulfur containing substituents represented by X bear the same type of groups.
  • X also represents the radical of an amine, e.g., an alkylamine like methylamine, ethylamine, dimethylamine, triethylamine, aralkylamine like dibenzylamine, pyridinium, l-quinolinium, l-picolinium, etc.
  • X and R may also join together, as indicated above, to fonn a bond linking carbon'and oxygen in a lactone ring.
  • heterocyclic groups represented by R are thienyl, furyl, pyridyl and isothiazolyl radicals as well as these heterocyclics with one or two substituents R, including halo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.
  • the salt forming ions represented by R may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, dibenzylamine, N ,N-dibenzylethylenediamine, methylamine, triethylamine, procaine, N-ethylpiperidine, etc.
  • the ester forming tri(lower alkyl)silyl and tri(lower alkyl)stannyl groups include, for example, trimethylsilyl, triethylsilyl, tri-n-butyl stannyl and the like.
  • R and R in addition to representing the individual substituents indicated may together be two or three methylene groups, (e.g., derived from ethylene glycol or propylene glycol) joining in a bridge which form a 5- or 6membered ring with the two oxygen atoms and 5 the phosphorus.
  • methylene groups e.g., derived from ethylene glycol or propylene glycol
  • the new [(thiophosphonothio)acetamidolcephalosporin derivatives of this invention are produced by reacting a 7-aminocephalosporanic acid compound of formula ll [which includes 7-aminocephalosporanic acid (7-ACA), 7-amino-3-desacetoxycephalosporanic acid (7-ADCA) and other derivatives], or an activated derivative, of the formula (II) with a dithiophosphoric acid ester of the formula (III) (III) R -CH-COOH l O-R S-P
  • the dithiophosphoric acid esters of formula III are produced by the following reaction n pa-coon S' O-R3 [The compounds of formula V are produced by the method described in Houben-Weyl, Methoden der Organischen Chemie, Vol. XII/2, pages 684-686 (1964)].
  • the halogen in the acid IV may be chlorine instead of 55 ambient temperature or below.
  • a product of formula I may be probromine and the sodium as well as potassiumsalt of V may be used.
  • R is the acyloxymethyl group
  • this group may be introduced into the 7-aminocephalosporanic acid moiety prior to the reaction with the dithiophosphoric acid ester or the activated derivative by treatment with one to two moles of a halomethyl ester of the formula (VI) halCH- OCOR wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like, at about cuted by reacting a compound of the formula (VI!) a in the presence of a tertiary alkylamine like triet hylamine, or with a salt of VIII, e.g., a metal salt such as an alkali metal salt, in a solvent such as dimethylformamide.
  • hal halogen, preferably chlorine or bromine
  • Hal is halogen, preferably chlorine or bromine and R and R are the same as above.
  • the metal salts are obtained by reacting a dithiophosphoric acid ester with the appropriate metal in a lower alkanol or with the metal alkoxide, e.g., potassium ethoxide.
  • the compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aurcus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris,Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins.
  • a com pound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about I to 200 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mgjkg. in mice.
  • Oral forms give prompt high blood levels which are maintained for relatively long periods.
  • a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets. capsules or elixirs or in an injectable form in a sterile aqueous 40 vehicle prepared according to conventional pharmaceutical practice.
  • compositions may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy equipment, at a concentration of about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying. They are also useful as nutritional supplements in animal feeds.
  • EXAMPLE 1 7-[2-[ (Diethoxythiophosphono)thio]acetamido]cephalosporanic acid and potassium salt ELIE 2 g. (5 mM) of 7-bromoacetamidocephalosporanic acid are dissolved in absolute dimethylformamide and a solution of 1.12 g. (SmM) of potassium dithiophosphoric acid 0,0 diethyl ester is added. A precipitate of potassium bromide forms immediately. After stirring for 10 minutes, the reaction mixture is poured into 250 ml. of ice water and extracted three times with 100 ml. portions of ethyl acetate. The ethyl acetate extracts are combined. shaken with 2 X 50 ml.
  • EXAMPLE 2 7-[ 2-[ Diethoxythiophosphono)thio]-2 phenylacetamidolcephalosporanic acid By substituting SmM of 7-(2-bromo-2- phenylacetamido)-cephalosporanic acid for the 7- bromoacetamidocephalosporanic acid in the procedure of Example I, there are obtained 2.] g. of yellow [(Dimethoxythiophosphono)thioIacetamidolcephalosporanic acid By substituting SmM of potassium dithiophosphoric acid By substituting SmM of potassium dithiophosphoric acid dimethyl ester for the diethyl ester in the procedure of Example 1, 1.2 g. of 7-[2- [(dimethoxythiophosphono)thio]acetamido]-cephalosporanic acid are obtained as a viscous oil.
  • EXAMPLE 4 7- 2-[ (Diethoxythiophosphono thio acetamido]-3- desacetoxycephalosporanic acid By substituting SmM of 7-bromo-3-desacetoxycephalosporanic acid for the 7-bromoacetamidocephalosporanic acid inthe procedure of Example I, there is obtained 7-[2- I(diethoxythiophosphono)thio]acetamido]-3- desacetoxycephalosporanic acid, m.p. 4814 50.
  • R is hydrogen, lower alkyl, phenyl-lower alkyl, 7.
  • R is hydrogen, tri(lower alkyl)silyl, tri( lower alkyl)stannyl, lower alkyl, alkali metal, trimethylsilyl or O O II II --CH -O-C-R CH O-CR 2 R and R each is lower alkyl; R, is lower alkyl; and aluminum, alkali metal, alkaline earth metal or tri(- X is hydrogen or acetoxy.
  • R is phenyl, R and R each is lower 8.
  • each alkyl group is methyl.
  • X is hydrogen, hydroxy or lower alkanoyloxy and R is hydrogen or alkali metal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Cephalosporin Compounds (AREA)

Abstract


WHEREIN R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group

R1 is hydrogen, lower alkyl, aralkyl, aryl or certain heterocyclic groups; R2 and R3 each is lower alkyl, aryl or aralkyl or R2 and R3 may together be two or three methylene groups joining in a 5- or 6-membered ring with the oxygen and phosphorus; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy,

THE RADICAL OF A NITROGEN BASE, A QUATERNARY AMMONIUM RADICAL, OR TOGETHER X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents.
((Thiophosphonothio)acetamido)cephalosporin derivatives of the general formula

Description

' United States Patent [1 1 Treuner et al.
[ Oct. 21, 1975 i 1 [(THIOPHOSPHONOTHIO)ACETAMIDO]- CEPI-IALOSPORIN DERIVATIVES [75] Inventors: Uwe D. Treuner, Regensburg;
Hermann Breuer, Burgweinting, both of Germany [57] ABSTRACT [(Thiophosphonothio)acetamido]cephalosporin derivatives of the general formula [73] Assignee: E. R. Squibb & Sons, Inc.,
Princeton, NJ.
[22] Filed: June 1, 1972 [21] Appl. No.: 258,687
[44] Published under the Trial Voluntary Protest Program on January 28, 1975 as document no.
[52] U.S. Cl. 260/243 C; 424/246 [51] Int. Cl. Q. C07D 501/20 [58] Field of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3,578,661 5/197] Havranek 260/243 C Primary Examiner-Nicholas S. Rizzo Attorney, Agent. or Firm-Lawrence S. Levinson; Merle J. Smith wherein R is hydrogen. lower alkyl. aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group R, is hydrogen, lower alkyl, aralkyl. aryl or certain heterocyclic groups; R; and R each is lower alkyl. aryl or aralkyl or R and R may together be two or three methylene groups joining in a 5- or 6-membered ring with theoxygen and phosphorus; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy.
the radical of a nitrogen base, a quaternary ammonium radical, or together X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents.
8 Claims, N0 Drawings [(THIOPHOSPHONOTHIO)ACETAMIDO]CEPH- ALOSPORIN DERIVATIVES SUMMARY OF THE INVENTION This invention relates to new [(thiophosphonothio)acetamido]cephalosporin derivatives of the formula ygen), hydroxy, carboxy and the likeiln the case of the last two named substituents there is preferably only" R represents hydrogen, lower alkyl, aralkyl, tri- (lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group -CH -O-C-R 7 R represents hydrogen, lower alkyl, aryl," aralkyl or certain heterocyclic groups; R and R5,; which a're preferably the same, each represents lower alkyl,'aryl or aralkyl or R and R may join together to form a 2 or 3 and carbon polymethylene bridge completing a 5- or 6- membered ring with oxygen and phosphorus; R represents lower alkyl, aryl or aralkyl. X is hydrogen, hy-
droxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy,
the radical of a nitrogen base, a quaternary ammonium radical, or together X and R represent a bond linking carbon and oxygen in a lactone ring.
The preferred members within each group are as follows: R is hydrogen, lower alkyl, alkali metal, trimethy lsilyl or ll -CH2-O-C-R4,
especially hydrogen, methyl, pivaloyloxy, sodium or potassium; R is phenyl, thienyl, furyl or pyridyl, especially phenyl, R, and R; each islower alkyl, especially methyl or ethyl; R is lower alkyl, preferably methyl or t-butyl; and X is preferably hydrogen or acetoxy.
DETAILED o sckiarioN OF THE INVENTION The various groups represented by the symbols have one, especially in the para position of the phenyl. Illustrative are phenyl, 0-, mand p-chlorophenyl, o-, mp-bromophenyl, 3,4-dichlorophenyl. 3,5- dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl. p-hydroxyphenyl, pcarboxyphenyl and the like.
The aralkyl groups include a monocyclic carbocyclic aryl group attached to a lower alkyl group, both as defined above. lllustrative are benzyl, o-, mor pchlorobenzyl, o-, mor p-bromobenzyl, o-. mor pmethylbenzyl, phenethyl, p-chlorophenethyl, 3,5- diethylbenzyl,3,4,5-trichlorobenzyl and the like.
The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented by X include the acyl group of acid esters. The lower alkanoyl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above. The lower alkanoyloxy groups include, for example, acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups are derived from monocyclic carbocyclic aryl groups of the kind described. Similarly the aralkanoyloxy groups consist of monocyclic carbocyclic aryl and alkanoyloxy radicals of the type described. The sulfur containing substituents represented by X bear the same type of groups. X also represents the radical of an amine, e.g., an alkylamine like methylamine, ethylamine, dimethylamine, triethylamine, aralkylamine like dibenzylamine, pyridinium, l-quinolinium, l-picolinium, etc. X and R may also join together, as indicated above, to fonn a bond linking carbon'and oxygen in a lactone ring.
The heterocyclic groups represented by R are thienyl, furyl, pyridyl and isothiazolyl radicals as well as these heterocyclics with one or two substituents R, including halo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.
The salt forming ions represented by R may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, dibenzylamine, N ,N-dibenzylethylenediamine, methylamine, triethylamine, procaine, N-ethylpiperidine, etc. The ester forming tri(lower alkyl)silyl and tri(lower alkyl)stannyl groups include, for example, trimethylsilyl, triethylsilyl, tri-n-butyl stannyl and the like.
R and R in addition to representing the individual substituents indicated may together be two or three methylene groups, (e.g., derived from ethylene glycol or propylene glycol) joining in a bridge which form a 5- or 6membered ring with the two oxygen atoms and 5 the phosphorus.
The new [(thiophosphonothio)acetamidolcephalosporin derivatives of this invention are produced by reacting a 7-aminocephalosporanic acid compound of formula ll [which includes 7-aminocephalosporanic acid (7-ACA), 7-amino-3-desacetoxycephalosporanic acid (7-ADCA) and other derivatives], or an activated derivative, of the formula (II) with a dithiophosphoric acid ester of the formula (III) (III) R -CH-COOH l O-R S-P The dithiophosphoric acid esters of formula III are produced by the following reaction n pa-coon S' O-R3 [The compounds of formula V are produced by the method described in Houben-Weyl, Methoden der Organischen Chemie, Vol. XII/2, pages 684-686 (1964)].
The halogen in the acid IV may be chlorine instead of 55 ambient temperature or below.
As an alternative, a product of formula I may be probromine and the sodium as well as potassiumsalt of V may be used.
4 (VII) or other activating compound such as dicyclohexylcarbodiimide, along with a salt forming organic base, such as triethylamine, pyridine or the like, followed, after an interval, by the addition of the 7-aminocephalosporanic acid compound. The product of the reaction is then isolated by conventional procedures, e.g., by concentration or evaporation of the solvent.
When R is the acyloxymethyl group this groupmay be introduced into the 7-aminocephalosporanic acid moiety prior to the reaction with the dithiophosphoric acid ester or the activated derivative by treatment with one to two moles of a halomethyl ester of the formula (VI) halCH- OCOR wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like, at about duced by reacting a compound of the formula (VI!) a in the presence ofa tertiary alkylamine like triet hylamine, or with a salt of VIII, e.g., a metal salt such as an alkali metal salt, in a solvent such as dimethylformamide. Hal is halogen, preferably chlorine or bromine and R and R are the same as above. The metal salts are obtained by reacting a dithiophosphoric acid ester with the appropriate metal in a lower alkanol or with the metal alkoxide, e.g., potassium ethoxide.
The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aurcus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris,Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a com pound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about I to 200 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mgjkg. in mice.
Oral forms give prompt high blood levels which are maintained for relatively long periods.
Up to about 600 mg. of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets. capsules or elixirs or in an injectable form in a sterile aqueous 40 vehicle prepared according to conventional pharmaceutical practice.
They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy equipment, at a concentration of about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying. They are also useful as nutritional supplements in animal feeds.
The following examples are illustrative of the invention. All temperatures are on the centigrade scale. Additional variations may be produced in the same manner by appropriate substitution in the starting material.
EXAMPLE 1 7-[2-[ (Diethoxythiophosphono)thio]acetamido]cephalosporanic acid and potassium salt ELIE 2 g. (5 mM) of 7-bromoacetamidocephalosporanic acid are dissolved in absolute dimethylformamide and a solution of 1.12 g. (SmM) of potassium dithiophosphoric acid 0,0 diethyl ester is added. A precipitate of potassium bromide forms immediately. After stirring for 10 minutes, the reaction mixture is poured into 250 ml. of ice water and extracted three times with 100 ml. portions of ethyl acetate. The ethyl acetate extracts are combined. shaken with 2 X 50 ml. portions of water, then dried over sodium sulfate and concentrated. There are obtained 1.5 g. of light yellow crystals of 7.-[2-[(diethoxythiophosphono)thio]acetamido]cephalosporanic acid, m.p. (dec.); potassium salt m.p. l l5 (dec.).
EXAMPLE 2 7-[ 2-[ Diethoxythiophosphono)thio]-2 phenylacetamidolcephalosporanic acid By substituting SmM of 7-(2-bromo-2- phenylacetamido)-cephalosporanic acid for the 7- bromoacetamidocephalosporanic acid in the procedure of Example I, there are obtained 2.] g. of yellow [(Dimethoxythiophosphono)thioIacetamidolcephalosporanic acid By substituting SmM of potassium dithiophosphoric acid By substituting SmM of potassium dithiophosphoric acid dimethyl ester for the diethyl ester in the procedure of Example 1, 1.2 g. of 7-[2- [(dimethoxythiophosphono)thio]acetamido]-cephalosporanic acid are obtained as a viscous oil.
EXAMPLE 4 7- 2-[ (Diethoxythiophosphono thio acetamido]-3- desacetoxycephalosporanic acid By substituting SmM of 7-bromo-3-desacetoxycephalosporanic acid for the 7-bromoacetamidocephalosporanic acid inthe procedure of Example I, there is obtained 7-[2- I(diethoxythiophosphono)thio]acetamido]-3- desacetoxycephalosporanic acid, m.p. 4814 50.
The following additional products having the formula in the right hand side of the table are obtained by the procedure of Example 1 from the potassium dithiophosphoric acid ester in the left hand part of the table and the 7-bromoacetamidocephalosporanic acid having the indicated R and X substituents.
9 10 What is claimed is: 6; A compound as in claim 5 wherein each alkyl 1. A compound of the formula group is ethyl.
S R -CH- CO NH CH -C|1H (Ill-I O-R 2 S-P N C-CH X l| O-R f 2 s OR wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, 7. A compound as in claim 1 wherein R is hydrogen, tri(lower alkyl)silyl, tri( lower alkyl)stannyl, lower alkyl, alkali metal, trimethylsilyl or O O II II --CH -O-C-R CH O-CR 2 R and R each is lower alkyl; R, is lower alkyl; and aluminum, alkali metal, alkaline earth metal or tri(- X is hydrogen or acetoxy. lower alkyl)amine; R is phenyl, R and R each is lower 8. A compound of the formula O-lower alkyl @TH- co-- NH CH CH (2H2 l s-P N C-CH x ll O-lower alkyl 0 4 2 S C-OR alkyl, phenyl-lower alkyl R, is lower alkyl, or phenyl lower alkyl; and X is hydrogen, hydroxy or lower al- 0 kanoyloxy.
2. A compound as in claim 1 wherein R and R each is lower alkyl.
3. A compound as in claim 1 wherein R and X each is hydrogen, R and R each is lower alkyl.
4. A compound as in claim I wherein R is hydrogen, R and R each is lower alkyl and X is acetoxy.
5. A compound as in claim 4 wherein each alkyl group is methyl.
40 wherein X is hydrogen, hydroxy or lower alkanoyloxy and R is hydrogen or alkali metal.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 v3 914 221 DATED October 21, 1975 INVENTOR(S) Uwe D. Treuner, Hermann Breuer It is certified'that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In the Abstract under the definition of X after anoyloxy should be inserted SR 0R Column 6, line 33 delete "By substituting 5mM of potassium dithiophosphoric acid" Column 6, line 51 delete "l4" and insert a hyphen Signed and Scaled this Nineteenth Day Of October 1976 [SEAL] A nest:
RUTH C. MnSON C. MARSHALL DANN Atteslmg Ojjr'cer (mnmissiuner uflarenls and Trademarks

Claims (8)

1. A COMPOUND OF THE FORMULA
2. A compound as in claim 1 wherein R2 and R3 each is lower alkyl.
3. A compound as in claim 1 wherein R and X each is hydrogen, R2 and R3 each is lower alkyl.
4. A compound as in claim 1 wherein R is hydrogen, R2 and R3 each is lower alkyl and X is acetoxy.
5. A compound as in claim 4 wherein each alkyl group is methyl.
6. A compound as in claim 5 wherein each alkyl group is ethyl.
7. A compound as in claim 1 wherein R is hydrogen, lower alkyl, alkali metal, trimethylsilyl or
8. A compound of the formula
US258687A 1972-06-01 1972-06-01 {8 (thiophosphonothio)acetamido{9 cephalosporin derivatives Expired - Lifetime US3914221A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US258687A US3914221A (en) 1972-06-01 1972-06-01 {8 (thiophosphonothio)acetamido{9 cephalosporin derivatives
US05/542,329 US3956290A (en) 1972-06-01 1975-01-20 [(Thiophosphonothio)acetamido]cephalosporin derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US258687A US3914221A (en) 1972-06-01 1972-06-01 {8 (thiophosphonothio)acetamido{9 cephalosporin derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US05/542,329 Division US3956290A (en) 1972-06-01 1975-01-20 [(Thiophosphonothio)acetamido]cephalosporin derivatives

Publications (2)

Publication Number Publication Date
USB258687I5 USB258687I5 (en) 1975-01-28
US3914221A true US3914221A (en) 1975-10-21

Family

ID=22981698

Family Applications (1)

Application Number Title Priority Date Filing Date
US258687A Expired - Lifetime US3914221A (en) 1972-06-01 1972-06-01 {8 (thiophosphonothio)acetamido{9 cephalosporin derivatives

Country Status (1)

Country Link
US (1) US3914221A (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3578661A (en) * 1969-06-02 1971-05-11 Bristol Myers Co Process for the preparation of 7-(alpha-(4 - pyridylthio)acetamido)cephalosporanic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3578661A (en) * 1969-06-02 1971-05-11 Bristol Myers Co Process for the preparation of 7-(alpha-(4 - pyridylthio)acetamido)cephalosporanic acids

Also Published As

Publication number Publication date
USB258687I5 (en) 1975-01-28

Similar Documents

Publication Publication Date Title
US3708479A (en) Acyloxymethyl esters of alpha-ureidocyclo-hexadie nylalkylene-cephalosporins
US3833568A (en) Heterocyclic ureidocephalosporins
US3741962A (en) Alpha-thioureidocephalosporanic acid compounds
US3886149A (en) Amino substituted dithiocarbonylthioacetyl cephalosporins
US3920639A (en) Cyanomethylthioacetyl-7-methoxycephalosporins
US3839329A (en) {60 -amidinothioacetamidocephalosporanic acid compounds
US3914221A (en) {8 (thiophosphonothio)acetamido{9 cephalosporin derivatives
US3855212A (en) Cyanomethylth ioacetylcephalosporins
US3989693A (en) 7-Methoxy cyclonexadienylureidocephalosporins
US3855211A (en) Dithiocarbonylaminoacetyl cephalosporins
US3846418A (en) Dithiocarbonylthioacetyl cephalosporins
US3796709A (en) (alpha-cyanamino)acetamidocephalosporins
US3767645A (en) Acylthioacetyl penicillins
US3880845A (en) Thiocarbonylthioacetyl cephalosporins
US3919205A (en) Dithiocarbonylthioacetyl cephalosporin derivatives
US3862941A (en) 2-(Thiocarbonylamino)acetamidocephalosporanic acid compounds
US3897423A (en) Amino substituted acylthio cephalosporins
US3956290A (en) [(Thiophosphonothio)acetamido]cephalosporin derivatives
US3870713A (en) Phosphono substituted alkylcephalosporins
US3926980A (en) Dithiocarbonylthioacetyl cephalosporins
US3875153A (en) Thiovinyl(thioacetamido) cephalosporins
US3944546A (en) Cyanomethylthioacetylcephalosporins
US3778436A (en) Acylthioacetyl cephalosporins
US3892735A (en) Cyanodithiocarbamic acid derivatives of cephalosporins
US3926979A (en) Dithiocarbonylthioacetyl cephalosporins